A versatile synthesis of substituted isoquinolines

Article abstract of DOI:10.1002/anie.201104769

Lithiated o-tolualdehyde tert-butylimines were shown to condense with nitriles to form eneamido anion intermediates that were trapped in situ with various electrophiles, thus affording a diverse array of highly substituted isoquinolines, many of which are

Full text of DOI:10.1002/anie.201104769

DOI: 10.1002/anie.201104769
Synthetic Methods
AVersatile Synthesis of Substituted Isoquinolines**
Chong Si and Andrew G. Myers*
In memory of David Y. Gin
In the context of a broader program directed toward the
synthesis of analogues of the isoquinoline-containing natural
product cortistatin A,[1,2] we wished to prepare a diverse array
of highly substituted isoquinoline coupling partners, but
routes to the complex heterocyclic structures we envisioned
were lengthy or impractical using classical[3] or more-
modern[4–6] methods. Herein we report a method for the
rapid construction of highly substituted isoquinolines of
extraordinary structural versatility; this method proceeds by
the convergent assembly of as few as two or as many as four
components in a single operation. Further substitutional
diversification can be achieved by modification of the work-
up conditions and by subsequent transformations, as detailed
below.
The present work was based on two important precedents.
The first was the synthesis of 3-substituted isoquinolones by
Poindexter; this synthesis proceeded by the addition of
nitriles to o-tolylbenzamide dianions followed by work-up
in the presence of ammonium chloride (Scheme 1).[7] The
second was the method of Forth et al. for the preparation of
ortho-substituted benzaldehyde derivatives by metalation of
o-tolualdehyde tert-butylimines, followed by alkylation of the
resulting anions, and then hydrolysis (Scheme 1).[8,9] We
imagined and quickly brought to practice the idea that the
trapping of metalated o-tolualdehyde tert-butylimines with
nitriles might provide a highly direct route to 3-substituted
isoquinolines. As we will show, the chemistry proved to be
much more versatile than we initially imagined; this versa-
tility is due to the transformations that ensue subsequent to
the addition of the nitrile.
Initial experiments established the feasibility of the
proposed construction in a simple system and provided
insights for expansion of the method. o-Tolualdehyde tert-
butylimine was metalated under the reaction conditions
specified by Forth et al., using stoichiometric n-butyllithium
and a catalytic amount of 2,2,6,6-tetramethylpiperidine in
tetrahydrofuran (THF) at 08C for 40 minutes, thus forming
the corresponding benzyl anion as a deep purple solution, as
previously reported.[8] Addition of this anion to a solution of
benzonitrile (1.5 equiv) in THFat À788C produced a dark red
solution within 3 minutes.[10] Upon warming to 238C the
reaction mixture became dark brown. Addition of saturated
aqueous ammonium chloride followed by extraction and
purification by flash column chromatography provided 3-
Scheme 1. The synthesis of isoquinolones reported by Poindexter and
the method of Forth et al. for metalation/alkylation of o-tolualdehyde
tert-butylimine. TMP=2,2,6,6-tetramethylpiperidine.
[*] C. Si, Prof. A. G. Myers
Department of Chemistry and Chemical Biology
Harvard University, Cambridge, MA 02138 (USA)
E-mail: myers@chemistry.harvard.edu
Scheme 2. A method for the direct condensation of o-tolualdehyde tert-
butylimines with nitriles to form substituted isoquinolines. The mech-
anistic pathway depicted accounts for the fact that addition of an alkyl
halide subsequent to condensation leads to the formation of 4-alkyl
substituted isoquinolines, exemplified by the formation of 4-methyl-3-
phenylisoquinoline.
[**] This research was supported by NIH grant CA-047148, stimulus
grant no. CA047148-22S1, and NSF grant CHE-0749566.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201104769.
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10409

Communications
phenylisoquinoline in 42% yield and, separately, 3,3’-
position, including ethyl iodide (entry 1), n-butyl iodide
(entry 2), allyl bromide (entry 3), and benzyl bromide
(entry 4). Although a number of potentially enolizable
aliphatic nitriles were successfully employed in this formal
[4+2] cycloaddition reaction, thus far acetonitrile has not
proven to be a viable coupling partner, most likely because
enolization is more rapid than addition to the nitrile.[15]
Entries 5–9 illustrate the use of N,N-dialkylcyanamides as
substrates; isoquinolines formed from the novel reagent N,N-
diphenyl-1,1’-biisoquinoline, in 35% yield (Scheme 2). The
latter by-product was imagined to arise by base-induced
dimerization of 3-phenylisoquinoline followed by oxidation, a
transformation for which there is some precedent.[11] By
adopting a different quenching protocol, that is, the addition
of excess trifluoroacetic acid at À78 then warming to 238C,
formation of 3,3’-diphenyl-1,1’-biisoquinoline was avoided
and 3-phenylisoquinoline could be isolated in 80% yield.
Mechanistically, we considered the
imido and tert-butylamido anions 1
Table 1: Condensation of lithiated o-tolualdehyde tert-butylimines with nitriles followed by electrophilic
trapping at the C4-position with various electrophiles provides an expedient synthetic route to multiply
substituted, structurally diverse isoquinolines.[a]
and 2, respectively (Scheme 2), to
be likely intermediates along the
pathway to 3-phenylisoquinoline
(although other pathways are pos-
sible), but neither species seemed
likely to account for the deep red
color that we observed upon addi-
tion of the o-tolualdehyde tert-buty-
limine anion to benzonitrile. We
speculated that the tert-butylamido
anion 2 might react further by intra-
or intermolecular proton transfer to
form an eneamido anion with
extended conjugation (3), and this
anion did appear to be a reasonable
candidate to account for the red
color we observed.[12–14] To test this
hypothesis methyl iodide (2 equiv)
was added to the deep red solution
shortly after its formation at À788C,
and an orange solution was pro-
duced within minutes. Addition of
Entry Imine
Nitrile
Electrophile
Product
Yield
[%][b]
1
EtI
52
50
2[c]
nBuI
3[d]
60
4
BnBr
50
52
66
54
5[d]
6[c]
7[d]
trifluoroacetic
acid
after
30 minutes, also at À788C, followed
by warming to room temperature,
aqueous work-up, and purification
by flash column chromatography
provided 4-methyl-3-phenylisoqui-
noline in 80% yield.
CH3I
Table 1 depicts a number of
examples of polysubstituted isoqui-
nolines that were synthesized by the
direct condensation of o-tolualde-
hyde tert-butylimine anions with
different nitriles followed by elec-
trophilic trapping at the C4-posi-
tion. For the metalation of halogen-
ated o-tolualdehyde tert-butyl-
imines the protocol of Forth et al.
led to decomposition, and instead
8[c,e]
NFSI
NFSI
C2Cl6
74
60
54
9[e]
10[f]
metalation
diisopropylamide
with
lithium
(LDA,
1.05 equiv) was effective for these
substrates (entries 2, and 8).
Entries 1–4 illustrate the use of
aliphatic nitriles as substrates and
show that a variety of alkyl halides
are suitable for alkylation at the C4-
11[g]
12[d]
MoOPH
40
68
6
CH3SSCH3
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Table 1: (Continued)
ble for subsequent diversification
at the C1-position (see below).
We have also found that with
tert-butylaldimine substrates con-
taining a second ortho-directing
group, such as a 3-fluoro substitu-
ent, it is possible to assemble
substituted isoquinolines from as
many as four components, added
in sequence, in a single operation.
For example, metalation of 3-
fluoro-5-(trimethylsilyl)benzalde-
hyde tert-butylimine with lithium
2,2,6,6-tetramethylpiperidide
(1.05 equiv) initially formed an o-
lithio intermediate that reacted
with methyl iodide (0.90 equiv;
Scheme 4). Subsequent deproto-
nation of the methylated product
in situ with lithium diisopropyl-
Entry Imine
Nitrile
Electrophile
Product
Yield
[%][b]
13[d]
55
[a] For transformations with enolizable nitriles as substrates (entries 1–4) 1 equiv of nitrile and
1.25 equiv of tert-butylaldimine were used; in most other cases 1 equiv tert-butylaldimine and 1.25–
1.5 equiv of nitrile were used. Metalation of the tert-butylaldimine was achieved by the method of Forth
et al.[8] [b] Yields of the isolated product. [c] With the halogenated tert-butylaldimine substrates lithium
diisopropylamide (LDA, 1.05 equiv) was used for metalation in lieu of TMP–nBuLi. [d] Hexamethyl-
phosphoramide (HMPA, 2 equiv) was added prior to the addition of the electrophile. [e] 1 equiv of
N-fluorobenzenesulfonimide (NFSI) and 1.25 equiv of tert-butylaldimine were used. [f] Electrophilic
trapping with hexachloroethane was conducted by addition of the reaction mixture by cannula to a large
excess of the electrophile (4 equiv) at À788C. [g] Potassium hexamethyldisilazide (KHMDS, 1 equiv)
was added just prior to addition of MoOPH (1.5 equiv). Bn=benzyl, MoOPH=oxodiperoxy-
molybdenum(pyridine)(hexamethylphosphoric triamide), PMB=para-methoxybenzyl, TMS=trime-
thylsilyl.
bis(p-methoxybenzyl)cyanamide in particular have proven to
be highly versatile intermediates for further elaboration, as
demonstrated below. Also, using N,N-dialkylcyanamides as
substrates we have shown that reactions at the C4-position
can be successfully achieved with Manderꢀs reagent,[16] thus
allowing introduction of a carbomethoxy group (entry 6) at
the C4-position, and that fluorination of the C4 atom is
possible by treatment with N-fluorobenzenesulfonimide (lim-
iting reagent; entries 8 and 9). Entries 10–13 exemplify
couplings with arylnitriles as substrates as well as reactions
at the C4-position to introduce other heteroatoms, including
chlorine (entry 10), oxygen (entry 11),[17,18] sulfur (entry 12),
and nitrogen (entry 13). In the latter two instances we found
that the efficiency of the reaction at the C4-position was
enhanced in the presence of the additive hexamethylphos-
phoramide (HMPA, 2 equiv). This additive also proved to
enhance the yield of C4-alkylation products in the cases of
entries 3, 5, and 7, a result which we believe is due to
acceleration of an otherwise slow proton-transfer reaction
that forms the eneamido anion intermediate.[21] In the absence
of HMPA C4-unsubstituted isoquinolines were formed as by-
products in each of these cases.
As illustrated in Scheme 3, it proved possible to obtain 4-
chloroisoquinolines, 1-tert-butylamino isoquinolines, and 4,4’-
biisoquinolines selectively by modification of the protocol for
the electrophilic trapping with hexachloroethane. Using a
substoichiometric amount of the electrophile (0.4 equiv,
added slowly) a 4,4’-biisoquinoline derivative was formed as
the primary product, a transformation that parallels a prior
observation reported by Mamane and co-workers.[12b] When
instead the putative eneamido anion was quenched by
addition to an excess of hexachloroethane (4 equiv) at
À788C 4,4’-biisoquinoline formation was avoided. Work-up
under standard reaction conditions, with trifluoroacetic acid,
led to the expected 4-chloroisoquinoline product. Impor-
tantly, using an alternative work-up procedure, that is, the
addition of diethylamine rather than trifluoroacetic acid,
elimination of hydrogen chloride occurred, thus forming a 1-
tert-butylamino isoquinoline derivative, which proved valua-
amide (1.05 equiv) at À408C, formed a dark red solution of
the presumed o-tolyl anion, and addition of benzonitrile,
followed by reaction at the C4-position with a second
Scheme 3. Selective preparation of 4-chloroisoquinolines, 1-tert-butyl-
amino isoquinolines, or 4,4’-biisoquinolines by variation of the con-
ditions of C4-trapping with hexachloroethane and subsequent work-up.
TFA=trifluoroacetic acid.
Scheme 4. In substrates with an appropriate ortho-directing group it is
possible to assemble substituted isoquinolines from as many as four
components in a single operation.
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Communications
equivalent of methyl iodide afforded 5-fluoro-4-
methyl-3-phenyl-7-(trimethylsilyl)isoquinoline in 45%
yield. A second example featuring a simpler, three-
component assembly is also illustrated in Scheme 4.
1-tert-Butylaminoisoquinoline (Scheme 3) and 3-
N,N-bis(p-methoxybenzyl)aminoisoquinoline deriva-
tives (Table 1, entry 9 and Scheme 4, bottom) were
found to be especially valuable intermediates for
further diversification, as were 7-trimethylsilylisoqui-
nolines (Table 1, entries 9-13). For example, treatment
of 4-fluoro-3-N,N-bis(p-methoxybenzyl)amino-7-(tri-
methylsilyl)isoquinoline with iodine monochloride in
dichloromethane at 08C afforded the product of 7-
iododesilylation, and[22] subsequent addition of tri-
fluoroacetic acid (neat) led to cleavage of the p-
methoxybenzyl groups to provide 3-amino-4-fluoro-7-
iodoisoquinoline in 75% yield (Scheme 5a). Diazoti-
zation of the latter product in the presence of fluoride
and chloride sources gave rise to the corresponding 3-
haloisoquinoline derivatives in good yield (Sche-
me 5a). Application of the same reaction sequence to
5-fluoro-3-N,N-bis(p-methoxybenzyl)amino-7-(trime-
thylsilyl)isoquinoline proceeded with chlorination at
the C4-position followed by a slower 7-iododesilylation
reaction during the initial treatment with iodine
monochloride;[23] subsequent transformations pro-
ceeded as expected to provide polyhalogenated iso-
quinolines, including the novel product 3-bromo-4-
Scheme 5. Preparation of halogenated isoquinolines from 1- and 3-amino-
isoquinolines obtained by the formal [4+2] cycloaddition of o-tolualdehyde tert-
butylimine with nitriles.
pp. 191 – 206; b) W. M. Whaley, T. R. Govindachari in Organic
chloro-5-fluoro-7-iodoisoquinoline (Scheme 5b). Lastly, we
observed that 1-tert-butylaminoisoquinoline derivatives, pre-
pared by condensation then chlorination with modified work-
up (see above and Scheme 3), are transformed directly into 1-
haloisoquinolines by dealkylative diazotization in the pres-
ence of halide ions. We anticipate the synthesis of a 1-
fluoroisoquinoline (Scheme 5c),[24] should allow for further
diversification at the C1-position by standard nucleophilic
aromatic substitution reactions.
The direct assembly of substituted isoquinolines and
biisoquinolines described herein provides a highly versatile
and uniquely enabling methodology for the construction of
these important heterocycles.[25]
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Received: July 8, 2011
Published online: September 9, 2011
Keywords: cyclization · nitriles · nitrogen heterocycles ·
.
o-tolualdehyde tert-butylimines · synthetic methods
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[14] An alternative sequencing of steps is feasible, e.g., tautomeriza-
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We thank a referee for suggesting this.
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